Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine genengn3

Hepatocyte nuclear factor 6 (HNF-6) is the prototype of a new class of cut homeodomain transcription factors. During mouse development, HNF-6 is expre ssed in the epithelial cells that are precursors of the exocrine and endocr ine pancreatic cells. We have investigated the role of HNF-6 in pancreas di fferentiation by inactivating its gene in the mouse. In hnf6(-/-) embryos, the exocrine pancreas appeared to be normal but endocrine cell differentiat ion was impaired. The expression of neurogenin 3 (Ngn-3), a transcription f actor that is essential for determination of endocrine cell precursors, was almost abolished. Consistent with this, we demonstrated that HNF-6 binds t o and stimulates the ngn3 gene promoter. At birth, only a few endocrine cel ls were found and the islets of Langerhans were missing. Later, the number of endocrine cells increased and islets appeared. However, the architecture of the islets was perturbed, and their beta cells were deficient in glucos e transporter 2 expression. Adult hnf6(-/-) mice were diabetic. Taken toget her, our data demonstrate that HNF-6 controls pancreatic endocrine differen tiation at the precursor stage and identify HNF-6 as the first positive reg ulator of the proendocrine gene ngn3 in the pancreas. They also suggest tha t HNF-6 is a candidate gene for diabetes mellitus in humans.